Nitro-trifluoromethyl-benzanilides

ABSTRACT

5-NITRO-3,3&#39;&#39;-TRIFLUOROMETHYLBENZANILIDES OF THE GENERAL CONFIGURATION IN WHICH R1 is H or CF3 and R2 is H or NO2 and veterinary compositions for the treatment of avian coccidiosis containing the same. The compounds 4&#39;&#39;,5-dinitro-3,3&#39;&#39;-(bis)trifluoromethylbenzanilide and 5-nitro-3,3&#39;&#39;,5&#39;&#39;-(tris)trifluoromethylbenzanilide are disclosed as illustrative examples.

United States Patent Welch et al.

[ Sept. 5, 1972 NITRO-TRIFLUOROMETHYL- BENZANILIDES [73] Assignee: Salsburg Laboratories [22] Filed: Nov. 18, 1968 [21] Appl. No.: 776,752

[52] US. Cl. ..260/558 P, 260/515 R, 260/544 M, 260/578, 424/324 [51] Int. Cl ..C07c 103/30 [58] Field of Search ..260/558 [5 6] References Cited UNITED STATES PATENTS 3,407,056 10/1968 Schwartz ..260/558 City,

Primary ExaminerJohn D. Randolph Assistant Examiner-Harry l. Moatz Attorney-Henderson & Strom [57] ABSTRACT 5-nitro-3,3'-trifluoromethylbenzanilides of the general configuration 0 H MQR,

CFa

3 Claims, No Drawings NITRO-TRIFLUOROMETHYL-BENZANILIDES This invention relates to new chemical compounds in the series of benzanilides in which the two nuclear rings are modified by the introduction of nitro (NO and trifluoromethyl (-CF substituents. More particularly, the compounds may be characterized by the following general configuration:

( l-I i R2 Fa OzN CFS in which R, and R may be identical or different, and R represents hydrogen or CF and R stands for hydrogen or N Illustrative and preferred embodiments of our invention are 4', 5-dinitro-3,3 bis)-trifluoromethylbenzanilide of the formula CFs O N CFa and 5-nitro-3,3 5 '-(tris)-triflu0romethylbenzanilide of the formula O N 0 Fri The compounds of our invention may be readily prepared by converting 3-trifluoromethyl-5- 40 nitrobenzoic acid with thionyl chloride into its benzoyl chloride and reacting the same with the desired fluoromethylaniline in accordance with the following equation:

2 EXAMPLE 1 4, 5-dinitro-3,3 -(bis)-trifluoromethylbenzanilide The formation of this compound proceeds in ac- 5 cordance with the following equation:

+ soon 3 ()ZN 013 OzN v on A mixture of 40 gms (0.169 mol) of '3- trifluoromethyl-S-nitrobenzoic acid and 200 ml of thionyl chloride was heated at reflux for 4%hours. The halogenating agent was thereupon removed under vacuum and the residue was added to a solution of 35 gms (0.169 mol) of 3-trifluoromethyl-4-nitroaniline in 150 ml of pyridine at a temperature below 25 C. The resulting solution was poured into 1 liter of water and yielded a precipitate which was removed by filtration. After recrystallization from aqueous alcohol about 47 gms (equal to percent of the theory) was harvested in form of yellow crystals. The compound has a melting point of l77-l7 8 C. and is soluble in most highly polar organic solvents. The substance on analysis was found to contain:

carbon 4l.96% (calculated value 42.57) hydrogen 1.58% (calculated value 1.67) nitrogen 9.58% (calculated value 9.93)

' EXAMPLE 2 5-Nitro-3,3',5'-(tris)-trifluoromethylbenzanilide The intermediate 3-trifluoromethyl-S-nitrobenzoyl chloride was prepared in accordance with Example 1 and the following equation illustrates the overall reaction:

GOCl

O N CF; E

OzN CF;

Thirty-nine grams (0.169 mol) of 3,5-( bis)- trifluoromethylaniline were dissolved in 150 ml of pyridine and treated with the benzoyl chloride intermediate of Example 1 at a temperature below 25 C. The mixture was poured into 1 liter of water and the resulting precipitate was filtered and recrystallized as a white solid from aqueous alcohol. The yield was 60 gms (equal to 80 percent of the theory) with a melting point carbon 43.13% (calculated value 43.06%) hydrogen l.56% (calculated value 1.58%) nitrogen 6.25% (calculated value 6.28%)

The compounds of our invention are useful in the prevention and control of poultry coccidiosis which is induced by a number of protozoal organisms. The most prevalent and injurious species responsible for this epizootic are Eimeria tenella, Eimeria necatrix, Eimeria acervulina, and Eimeria brunetti, which differ in degree of virulence and may cause a variety of clinical symptoms, from a lingering state of morbidity, unthriftiness, and marasmus to a ruinous decimation of entireflocks by a substantial death toll.

In accordance with another aspect of our invention therefore, we provide veterinary compositions containing the above-identified chemicals as active ingredients for the control of avian coccidiosis. The drugs are advantageously employed by introducing the same into theanimal organism in any form or manner in which they are capable of building up and maintaining an effective blood and tissue level. This can be accomplished either by injection or by dispensation of suitable nontoxic dosages in capsules or tablets. However, as a preferred embodiment, we use as a carrier material, a liquid or solid food such as a drinking water solution or suspension, or any commercial feed ration of the starting, growing, or laying type which will supply the basic nutritional requirements of the birds. The somedicated rations are placed before the birds for consumption ad libitum.

The minimum dosages in the feed run from 0.00625 to 0.1 percent depending upon the parasite to be checked, the gravity of the outbreak, and the specific drug employed. The preferred ranges for 4', S-dinitro- 3,3'-( bis)- trifluoromethylbenzanilide are from 0.025-0.05 percent and for 5-nitro-3,3,5'-( tris)- trifluoromethylbenzanilide from 0.01250.05 percent. The following tables will illustrate the utility of our new compounds.

For each experiment, perfectly healthy 4l-week-old Leghorn chickens, in groups of four, were reared in an aseptic environment and prepared for test fitness. Each bird was weighed starting on the first and continuing to the last day of the experiment. In order to determine the efficacy of the drug, each of the birds was placed on medicated food at least two days before artificial inoculation and successively maintained thereon for 8 to 13 days. For artificial challenges, the birds received, respectively, 540,000,000 oocysts of Eimeria acervulina, 200,000 oocysts of Eimeria brunetti, and 100,000 oocysts of Eimeria necatrix, and Eimeria tenella. A reference group of four birds was infected but left without medication and served as controls. A third group of four birds was neither challenged nor treated with medicated rations. The activity of the drugs was evaluated in terms of comparative fecal scores and morbidity factors, and in the case of E imeria tenella and Eimeria necatrix of mortality rates.

By way of explanation, the two columns following the test number record the specific parasite against which the compound was tested and the dosage level in the feed employed. The tests in which no feed concentration is given apply to infected, untreated controls and serve as basis of comparison. The fecal scores are expressed in percentages and computed in the following manner. Beginning on the fourth day after experimental inoculation and every day thereafter until the conclusion of the experiment, the droppings of each bird were carefully examined and their deviations from the normal appearance were graded in accordance with accepted practice as fecal scores, which were computed in the following manner. In the case of Eimeria tenella the amount of hemorrhage in the droppings collected in metal pans beneath the birds were rated and recorded in terms of:

0 no hemorrhage B slight hemorrhage BB moderate hemorrhage BBB severe hemorrhage BBBB very severe hemorrhage Upon the conclusion of the test, the maximum hemorrhage rating for each bird, irrespective of the day of its occurrence, was recorded. All the maximum ratings for the medicated, infected groups were totaled and compared with the total of the maximum ratings of the nonmedicated, infected controls. If the artificial infections had taken effective hold, each of the four infected and nonmedicated birds would show a full rating of 4 Bs during at least one day of the test period so that the maximum total rating for that group would usually amount to 16 Bs. Supposing the highest ratings for four infected and medicated birds in a given group are, respectively, 0, BB, B, and B, the total rating for the entire group would be 4 Bs. The difference between the B-totals divided by the maximum rating established for the infected, nonmedicated controls times 100 represents the fecal score; thus, 16 4 12; 12/16 X 100 A fecal score of 75 percent, therefore, means that the droppings were 75 percent normal.

Similarly the fecal scores for the species causing no appreciable hemorrhage, but other characteristic clinical deviations in the droppings, are computed on the basis of their magnitude in terms of the following ratings:

0 droppings normal droppings slightly abnormal droppings about half normal -H-ldroppings about one quarter normal Hl-+ droppings completely abnormal The mortality column in the table records first the actual number of birds out of four which succumbed to the infection and the corresponding death toll in percentages.

MF stands for Morbidity Factor. This criterium expresses the comparative values between the mean weight gains of noninfected, nonmedicated birds and those of the infected nonmedicated birds, or, respectively, the infected, medicated test animals. During the 5th to 7th day the coccidial infection usually causes the maximum inhibition of growth which reflects itself in the ultimate weight gains or losses at the conclusion of the test periods. Assuming the mean weight gain of the uninfected, nonmedicated birds is 200 gms, equal to percent, and that of the infected, nonmedicated controls is 28.6 gms, the morbidity factor would be (28.6/200) X 100 14.3%, which indicates that due to the infection the growth rate has reached a level of only 14.3 percent, or, conversely, has dropped by 100 14.3% 85.7% from the normal. This figure is listed in the succeeding column titled GRD (Growth Rate Drop). If, on the other hand, the morbidity factor of the infected, medicated group is 64.8 percent, the corresponding GRD would be only 35.2 percent. The difference between the two morbidity factors, or 85.7 35.2% 50.5%, signifies that as a result of the medication a growth rate increase of 50.5 percent was achieved over the infected, nonmedicated controls, or that the stunting effect of the infection was compensated by the drug to the extent of 50.5 percent. This figure appears in the last column as compensating effect, or CE. In some of the tests, as for example Eimeria tenella, no comparative morbidity factors and compensating effects could be established because the infected animals died before they could be weighed. This also occurred occasionally at the toxicity threshold of the O N CFS wherein R represents H or CF and R represents H or N0 2. 5,4-dinitro-3,3-(bis)-trifluoromethylbenzanilide. 3. 5-nitro-3,3, 5-( tris)-trifluoromethylbenzanilide.

maximum dosage level of 0.1 percent in relation to the TABLE I (4, 5 dinitro-3, 3-(bis) trifluoromethylbenzanilide) Mortality Feed Focal conc., score, N0. MF, GRD, CE, Parasite percent percent deed Percent percent percent percent 0 1 0 0 0 0 3 75 -4. 104.2 0 0 42. 7 57.3 0 0 0 57. 7 42.3 100 0 0 71. 0 29. 0 acerzmlin 0 0 0 38.2 61.8 acervulina. 90 0 0 75.1 24. 9 acervulina. 0 0 0 14. 3 85. 7 E. acervulina. 0 0 64. 8 35. 2 acervulina- 100 0 0 88. 5 11. 5 acervulina. 100 0 0 81.0 19.0 acervulina 0 0 0 33. 4 66. 6 acervulimz 100 0 0 75. 9 24. 1 brunetti 0 0 0 24. 1 75. 9 E. brunetti- 0 0 73.0 27.0

TABLE II (5'-nitro-3, 5, 3-(tris)-trifluoromethylhenzani1ide) Mortality Feed Fecal c0110., score, No. MF, GRD, GE, Parasite percent percent dead Percent percent percent percent 0 0 0 12. 9 100 0 0 53.2 0 0 0 33.0 5 0 0 43.2 acervulinm 0 0 58.6 acervulina- 0.0250 100 0 0 83. 3

0.0500 100 0 0 0.1000 100 0 0 0 0 0 0. 0500 100 0 0 0 0 0 0.00625 25 0 0 0.01250 0 0 0.02500 0 0 0.0500 100 0 0 26 E brunettt 0.1000 100 0 0 

2. 5,4''-dinitro-3,3''-(bis)-trifluoromethylbenzanilide.
 3. 5-nitro-3,3'', 5''-(tris)-trifluoromethylbenzanilide. 